Synthesis of vitamin a and intermediates therefor



' vitamin A acid was produced.

atented Oct. 28, I952 if: I a;

UNITED STATES PATENT OFFICE SYNTHESIS OF VITAMIN A AND INTERMEDIATESTHEREFOR Albert Carl Starke, Jr., Easton, Pa., assignor to GeneralAniline & Film Corporation, New York, N. Y., a corporation ogllelawareNo Drawing. Application December 17, 1949, Serial No. 133,663

11 Claims. (01. 260-598) 1 2 This invention relates to the synthesis ofvita- I have now discovered that vitamin A and valu min A and of novelintermediates therefor. able intermediates therefor can be prepared fromIn accordance with the disclosure of Van Dorp the aforesaid Cm ketone bya, different procedure, et al. (Rec. Trav. Chim. des Pays-Bas, 65, 1946,constituting a highly convenient and economical page 338), a vitamin Aacid, showing biological 5 method for the synthesis of vitamin A andinteractivity, was prepared from fi-ionone. The pr mediates therefor.cedure involved condensation of B-ionone with 9 It is accordingly anobject of my invention to -bromocrotonic acid ester in the presence ofprovide a novel procedure for preparing vitamin zinc, dehydration andsaponification of the re- A, and further, to provide a series of novelintersulting hydroxy ester to ionylidene crotonic acid, 10 mediates forthis procedure. and reduction of the latter with lithium methyl, Inaccordance with my invention, the C18 kefollowed by hydrolysis, to forma C18 ketone hav- -73. tone, formulated above, is treated with anorthoing the following formula: ester of a carboxylic acid, especiallyan ortho- OH CH formate, to form the corresponding ketal. The on, latteris then condensed with a vinyl ether in the presence of an acidcondensing a ent, to form an ether acetal, which yields vitamin Aaldehyde H CH3 upon hydration and dealcoholation. Vitamin A aldehyde, onreduction, yields the corresponding H1 20 alcohol, which is vitamin A:By condensation of this ketone with bromoacetic CH3 CH3 ester in thepresence of zinc, and dehydration 0H, and sapomfication of the resultinghydroxy ester, H2 E,

According to Schwarzkopf et al. (Helv. Chim. H

on Acta, 32, 1949, page 452), the ester of vitamin A acid, produced bythe foregoing procedure was I reduced to vitamin A (the correspondingalcohol) The reactions involved in the procedure of this by reductionwith lithium aluminum hydride. invention are as follows:

According to Dutch Patent 62,738, the afore- 1. Reaction of the C18ketone with an orthosaid C18 ketone can be converted to an aldehydecarboxylic ester:

CH: CH: OH; H; CH=CH-C=CH-CH=OHCOCH: R-C(0R)= f g H OH:

CH: CHa

CH: 0R H2 CH=CH=CHCH=CH-i-CH: R'COOR H OH: R

of the vitamin A series by reaction with metallo (B being an alkylgroup, and R'CO- reprederivatlves or Grignard reagents of alkylor Isenting the radical of an organic carboxy acid).

aryl-oxyacetylene, followed by selective reduction acid condensation ofthe acetylenic bond to an olefinic bond, or by H=OH1 reaction of theketone directly with a metallo de- CH rivative of an alkylor anaryl-oxyethene, fol- I 0H3 lowed by hydrolysis of the alkylor aryl-oxygroup, accompanied by rearrangement to form R the desired hydroxyaldehyde of the vitamin A H series. The latter can be hydrated andhydro- H:

; genated to obtain vitamin A. (the Rs representing alkyl groups)2,616,9 1 3 4 CH CH 3 X 8 CH8 362 t 1 i i tf th t 1 .pars .mo)oeeeraceapro- +1110 H2 CEOHJLCH CECE CHO+3ROH duced in Example 2 aremixed with 3.6 parts (0.2

mol) of water containing- 0.05 part of paratoluene sulfonic acid. Themixture is heated in H! a distillation apparatus provided with afraction- The aldehyde thus produced can be reduced to ating column inan inert atmosphere (e. g. nitrovitamin A, e. g. by reaction withaluminum isogen) to 50 C., and vigorously agitated at this propylate, asindicated by the following reaction: temperature for one-half hour. Thetemperature cm on; OH: @H.

CH3 CH2 H CH: H. (2H3 Hz H2 amin A) I is then gradually raised to 65 C.until distillation The following Series of examples illustrate ofmethanol virtually ceases. The residue is then ferr d procedures whichmay be employed f r taken up in ether, the ethereal solution washedcarrying out the process of my invention. Parts with dilute aqueoussodium carbonate, then with are by Weight unless otherwise indicated.The water, and then dried over anhydrous sodium sulnumbers of theexamples correspond to the fate. These operations are preferably carriedout her of the e nations set Out above while maintaining an atmosphereof nitrogen or S q other inert gas. The ether is evaporated from Example1 the solution in the inert atmosphere, leaving as a 25.8 parts (0.1mol) of the C ket ne, forrnqresidue, vitamin A aldehyde having thefollowing lated above, and prepared by the procedure of formula:

Van Dorp et a1. (loo. cit.), are mixed with 21.2

parts (0.2 mol) of methyl-ortho-formate con- 5 rm V taining 0.05 part ofthe diethyl ether complex of H, orr2on-c=ch-oh=cu-c=on cno BF: (1. e.,BF: etherate) at a temperature pf 25 to 45 C. The reaction mixture isallowed to H, on,

stand for 2 to 3 hours at a temperature wittlil in the latter ran e. Thereaction mixture is en 7 dissolved in 5 and the BF3 catalyst neutra1 Inorder to prepare vitamin A, the aldehyde ized with a Small amount ofSodium ethylatpe or obtained according to Example 3 (about 30 parts)ethanolamine. The ether solution is washed with can be dlssolved 300parts of 2 9 Water separated from the aqueous layer and alcohol, thesolution heated to boiling in a mtrodried over anhydrous sodium sulfate.The ether gen atmosphfare reflux apparatus and and the volatilecomponents of the mixture are parts of alummum Pp l added 0 hem):-removed by distillation and the higbboflmg ture. Isopropyl alcohol isradually distilled from residue is fractionated by distillation underhig the mlxture and replaced thelien} wlthyfresh ly reduced pressure (aS0 ca11ed mo1ecu1ar propyl alcohol. When the distillate no longerdistillation) to obtain the dimethyl ketalcorreylelds aposltl"? t 9? a eby spending to the C18 ketone, having the formula. tion of crystallinepara-nitrophenyl hydrazone on treatment with a solution ofpara-mtrophenyl- CH3 fi hydrazine in glacial acetic acid) the mixture iscooled, diluted with petroleum ether (B. P. 30 to 40 0.), and extractedwith 5% aqueous phos- CHI phorous acid. The aqueous extract is extractedwith additional petroleum ether, and the com- H, bined petroleum etherextracts are dried over an- Emmpze 2 hydrous sodium sulfate, yielding asolution of vitamin A which can be recovered by chromatoparts mol) medlmethyl F of graphic absorption from the petroleum ether sothe Cirketone, produced in accordance with the lution on aluminum oxide andelutriavted fmm plecedmg example are mlxed Wlth 9 p s the adsorbent witha mixture of benzene and pe- (0-0095 mol) of BF? etheraten The mlxturetroleum ether. A pure product can be obtained in heated 130 and 2 mol)of methyl this manner having properties similar to vitamin vinyl etherare gradually introduced over a pe- A obtained from natural sources.

riod of 15 minutes. The reaction mixture 18 In carrying out the VariousSteps of the stirred at 45 6 for hours, cooled cedure illustrated in theforegoing examples, nuand the BF3 Catalyst neutrahzed by addmon ofmerous variations and modifications can be made. small amount of sodiummethylate. The reach Thus, in the procedure of Example 1, the orthotionmixture 1S fractionally dist lled under lug ly ester employed forconversion of the C18 ketone reduced pressure (molecular distillation)totfieto the wrrespondmg ketal can be an Ortho ester cover separatefractions of the unreacted dime yl of a lower fatt carbox V i th ketal,and the reaction product which is a methyl y y ac d Her an formlc acid,e. g. it can be anortho-acetate, orthoether ace al havmg the followmgformula propionate or ortho-butyrate. The 'ortho ester H, CH3 Y maycontain the radicals of other monohydric (1H3 (3H3 alcohols than methylalcohol, e. g. ethyl, propyl, H CH:CHC=GHOH=CH-CCHz-CH(0CH5): butyl orbenzyl alcohol. Ortho esters of lower I aliphatic carboxy acids can alsobe used in which EV CH; the esterifying alcohols include a dihydricalcohol H, such as 1,3-propanediol, together with a monoether.

hydri'c alcohol, asfound, for example, in'Z-ethoxy-1,3-dioxolane, whichis an ortho-formic ester of ethyl alcohol and l,3-propanediol.. Orthoesters of methyl alcohol are preferred in order to maintain themolecular weight of the resulting ketal as low as possible, and therebyfacilitate its purification by distillation.

The proportions of the ortho ester and the Cm ketone can be varied, butit is convenientto employ a molecular excess of ortho ester with respectto the ketone, a mol ratio of about 2:1 beingsuitable, as illustrated inExample V1. p

An acid condensation catalyst is employed to promote ketal formation,such catalysts including BFs, BFa etherate, BC13, SnCh, 'TiCh, or H2804,or acid-reacting salts such as ammonium chloride or ammonium nitrate, asuitable proportion of catalyst being from 0.0001 to 0.01 mol per mol ofortho ester. The temperature employed in this reaction can vary from to50 C. Higher temperatures within this range tend to. accelerate thereaction, and in general, provide more satisfactory operatingconditions.

The methyl vinyl ether employed in Example 2 is preferred, but can bereplaced by other vinyl ethers, such as the corresponding ethyl, propyl,isopropyl, butyl and benzyl ethers. The condensation reaction of thisexample is carried out under anhydrous conditions. An inert solvent ordiluent can be used, but it is more advantageous to bring the reagentstogether in the absence of a diluent so as to afford maximum opportunityfor rapid combination'of the ketal with the vinyl To limit undesirableside reactions-especially polymerization of the vinyl ether, asubstantial excess of the ketal is preferably maintained in the reactionmixture throughout the condensation. Thus, in general, it is preferredto employ at least 2 and preferably about 3 mols of the ketal for eachmol of vinyl ether introduced. By reason of the inhibition ofolymerization of the vinyl ether, a higher ultimate yield can beobtained when the unreacted ketal is recovered and recycled to asubsequent condensation.

The condensation reaction of Example 2 is promoted by inclusion ofacid-reacting anhydrous condensing agents as catalysts, as, for example,those used in Example 1. The'proportion of catalyst employed can be from0.0001 to 0.1 mol per mol of the ketal, and is preferably between 0.0025and 0.01 mol. The temperature of the condensation can be varied between0 to 100 C., but is preferably not higher than 50 C. Vinyl methyl ether(B. P. 5 to 6 C.) is a gas at room temperature, while higher molecularweight ethers are liquids. ,When the temperature. employed is such thatthe vinyl ether is relatively volatile, superatmospheric pressure can beused to avoid excessive volatili'zation tion mixture.

In carrying out the dealcoholation and hydrolysis of the ether ketalproducedv by condensation of the vinyl ether with the ketal of the Cmketone, as illustrated in Example 3, water isadded to the etheracetal'i'n at least an equim'olecular amount. The amount ofwateradded inexcess is not critical, liowevenbutit is convenient to add 2 to 3 molsof water per'molof ether acetal.

A water-soluble acidic substance'is employed as a catalyst for thehydrolysis and dealcoholation, preferably an organic non-volatile acidsuch as para-toluene sulfonic acid; However, other organic acids such asacetic acid can be" 'used,*or inorganic acids such as I-ICl, I-I 2SO4,'HsPCr, or

of the'ether'from the reacwater-soluble acid-reacting salts-such asNHiCl,

6 ZnClz, NaI-ISCi, and the'like. The, amount of acid thus used is small,amounting, for example, to'0.00l to 0.1 mol per mol of water. Thetemperature is advantageously maintained at 50 to C. In general, thetemperature is preferably maintained at about the boiling point of thealcohol to be eliminated, within the aforesaid range. Since this stepinvolves formation of a poly-unsaturated aldehyde, oxygen is preferablyexcluded during the reaction and the subsequent treatment, to avoidexcessive losses from oxidation or polymerization of theproduct.

.-In preparing vitamin A from the vitamin A aldehyde, produced by theaforesaid dealcoholation and hydrolysis, an aluminate of a secondaryalcohol (e. g. isopropanol, 2-butanol, or 2- or 3- pentanol) can beused. Aluminum isopropylate is particularly well suited, since thealcohol corresponding thereto, as well as the acetone produced therefromare volatile and water-soluble, and can be readily removed from thereaction product by aqueous extraction. The reduction of the vitamin Aaldehyde to vitamin A is carried out in alcoholic solution underanhydrous conditions, and the final product can be recovered, asindicated above, by extraction with hydrocarbon solvents. Othervariations and modifications which will be obvious to those skilled inthe art can be made in the foregoing process without departing from thespirit or scope of this invention.

I claim: 1. In a process for the synthesis of vitamin A or of anintermediate therefor, the steps-Which comprise reacting a ketone havingthe following formula:

with an ortho-carboxylic acid ester to form the corresponding ketal,condensing the resulting ketal with 1 molecular equivalent of a vinylether to form an ether acetal having the following formula:

wherein the R's represent alkyl groups, and simultaneouslydealcoholizing and hydrolyzing said ether acetal to form a polyolefinicaldehyde which yields vitamin A upon reduction with an aluminumalcoholate of a secondary alcohol.

2. In a process for the synthesis, of vitamin A or of an intermediatetherefor, the step which consists in reacting a C18 ketone having thefollowing formula:

with an ortho-carboxylic acid ester in the presence of an acidcondensation catalyst to form the corresponding ketal.

3. A process as defined in claim 2, wherein the ortho-earboxylic acidester is methyl-ortho-formate and the catalyst is BF: etherate.

ears-see 4'. In a process for the synthesis of vitamin A or or anintermediate therefor, the step which consists in condensing a ketalhaving the following formula:

CH1 OH;

wherein R represents an alkyl group, with a vinyl alkyl ether in thepresence or an acid condensation catalyst, to form an ether acetalhaving the following formula:

CH: CH3 i cm on,

' CH OH=* CH CH=CH U-CFPCH(0 R);

wherein the Rs represent alkyl groups.

5. In a process for the synthesis of vitamin A or of an intermediatetherefor, the step which consists in heating an ether acetal having thefollowing formula:

CH3 CH3 7 V CH; (1TH: n. -cH=cn on crhon c onwcn( R wherein the Rsrepresent alkyl groups, with at least an equimolecular amount of waterin the presence of a water-soluble acidic substance as the catalyst at atemperature of 50- to 100 0., in. an inert non-oxidizing atmosphere,whereby said ether acetal is converted to a polyolefinic aldehyde havingthe formula:

CH3 CH8 CH3 CH3 6. A ketal having the following general formula:

CH9 CH3 CH: 03

cH=oH-c :=cH-oi1=cH-( 2-om H CHs wherein the R's represent alkyl groups'7. An ether acetal having the formula:

H OH:

wherein the R's represent alkyl groups.

8. A ketal having the following formula:

9. ether acetal having the rollowing' for inula;

CH: CH:

10. in a processror th synthesis or vitamin A or of an intermediatetherefor, the step which consists in condensing a ket'al having thefollowing rormula:

with vinyl methyi ether in the presence of EFs etherate as the catalystto form an ether acetal having the following formula:

CH: CH:

1L. in a process for the synthesis of vitamin A or of an intermediatetherefor. the step which consists in heating an ether acetal having. thefollowing formula:

ALBERT CARL: STARKE, J R1 REFERENCES CITED The following references areof record in the file ofthis patent:-

UNITED STATES PATENTS Number Name Date 2,48'L525 Copenhaver' i Nov. 8,i949 Number Country Date 744,344 France a- Apr. 18 1933 OTHER REFERENCESWhitmore-s Organic Chemistry, page 341, Van Nostrand 00., N. Yr(.1937).-

Van=Dorp ct al-., Rec. Trav.- Ghirndes Pays-Bas, v01. 65, page 338-(-1946).

1. IN A PROCESS FOR THE SYNTHESIS OF VITAMIN A OR OF AN INTERMEDIATETHEREFOR, THE STEPS WHICH COMPRISE REACTING A KETONE HAVING THEFOLLOWING FORMULA: